U.S. patent application number 13/829304 was filed with the patent office on 2014-09-18 for oxamazin antibiotics.
The applicant listed for this patent is Rempex Pharmaceuticals, Inc.. Invention is credited to Tomasz Glinka, Scott Hecker, Olga Rodny.
Application Number | 20140275007 13/829304 |
Document ID | / |
Family ID | 51529928 |
Filed Date | 2014-09-18 |
United States Patent
Application |
20140275007 |
Kind Code |
A1 |
Glinka; Tomasz ; et
al. |
September 18, 2014 |
OXAMAZIN ANTIBIOTICS
Abstract
Disclosed herein are oxamazin monobactam compounds and their use
as antibiotics resistant to degradation by .beta.-lactamases. Also
disclosed are pharmaceutical compositions containing the compounds
and methods of synthesis.
Inventors: |
Glinka; Tomasz; (Cupertino,
CA) ; Hecker; Scott; (Del Mar, CA) ; Rodny;
Olga; (Mill Valley, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Rempex Pharmaceuticals, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
51529928 |
Appl. No.: |
13/829304 |
Filed: |
March 14, 2013 |
Current U.S.
Class: |
514/210.15 ;
540/355 |
Current CPC
Class: |
C07D 205/085
20130101 |
Class at
Publication: |
514/210.15 ;
540/355 |
International
Class: |
C07D 205/085 20060101
C07D205/085 |
Claims
1. A compound having the structure of formula I: ##STR00057## or a
pharmaceutically acceptable salt thereof, wherein: R.sup.1 and
R.sup.2 are independently selected from the group consisting of H,
halide, CN, C.sub.1-3 alkyl, --X(C.sub.1-3 alkyl), --(C.sub.1-3
alkyl)OH, --(C.sub.1-3 alkyl)CN and C.sub.1-3 haloalkyl, or
alternatively R.sup.1 and R.sup.2 together with the atom to which
they are attached form a three to four membered carbocyclic ring
optionally substituted with one or more halide, or a four membered
heterocyclic ring; R.sup.3 and R.sup.4 are independently selected
from the group consisting of halide, CN, C.sub.1-3 alkyl,
--X(C.sub.1-3 alkyl), --X(C.sub.1-3 haloalkyl), --(C.sub.1-3
alkyl)OH, --(C.sub.1-3 alkyl)CN and C.sub.1-3 haloalkyl, or
alternatively R.sup.3 and R.sup.4 together with the atom to which
they are attached form a three to four membered carbocyclic ring
optionally substituted with one or more halide, or a four membered
heterocyclic ring; R.sup.5 and R.sup.6 are independently selected
from the group consisting of H, halide, CN, C.sub.1-3 alkyl,
--X(C.sub.1-3 alkyl), --X(C.sub.1-3 haloalkyl), --(C.sub.1-3
alkyl)OH, --(C.sub.1-3 alkyl)CN and C.sub.1-3 haloalkyl, or
alternatively R.sup.5 and R.sup.6 together with the atom to which
they are attached form a three to four membered carbocyclic ring
optionally substituted with one or more halide, or a four membered
heterocyclic ring; A is selected from the group consisting of C--H,
C-halide, and N; and each X is independently selected from O or
S.
2. The compound of claim 1, wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, halide, CN,
C.sub.1-3 alkyl, --(C.sub.1-3 alkyl)CN, --(C.sub.1-3 alkyl)OH, and
C.sub.1-3 haloalkyl, or alternatively R.sup.1 and R.sup.2 together
with the atom to which they are attached form a three to four
membered carbocyclic ring optionally substituted with one or more
halide, or a four membered heterocyclic ring.
3. The compound of claim 1, wherein R.sup.1 and R.sup.2 are H.
4. The compound of claim 1, wherein R.sup.1 is H and R.sup.2 is
selected from the group consisting of halide, CN, C.sub.1-3 alkyl,
--(C.sub.1-3 alkyl)CN, --(C.sub.1-3 alkyl)OH, and C.sub.1-3
haloalkyl.
5. The compound of claim 4, wherein R.sup.2 is selected from the
group consisting of CN, CH.sub.3, CH.sub.2OH, CH.sub.2CN and
CH.sub.2F.
6. The compound of claim 1, wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of halide and
C.sub.1-3 alkyl.
7. The compound of claim 1, wherein R.sup.1 and R.sup.2 together
with the atom to which they are attached form a three to four
membered carbocyclic ring optionally substituted with one or more
halide, or a four membered heterocyclic ring.
8. The compound of claim 7, wherein R.sup.1 and R.sup.2 together
with the atom to which they are attached form a ring selected from
the group consisting of cyclobutyl, 3-fluoro-cyclobutyl,
2-oxetanyl, and 3-oxetanyl.
9. The compound of claim 1, wherein R.sup.3 and R.sup.4 are
independently selected from the group consisting of C.sub.1-3 alkyl
and --(C.sub.1-3 alkyl)OH.
10. The compound of claim 1, wherein R.sup.3 and R.sup.4 are
independently selected from the group consisting F, CH.sub.3,
CH.sub.2F, CHF.sub.2, CN, OCH.sub.3, SCH.sub.3, OCH.sub.2F,
SCH.sub.2F, OCHF.sub.2, SCHF.sub.2, and CH.sub.2CN.
11. The compound of claim 1, wherein R.sup.3 and R.sup.4 together
with the atom to which they are attached form a ring selected from
the group consisting of cyclobutyl, 3-fluoro-cyclobutyl,
2-oxetanyl, 3-oxetanyl, and cyclopropyl.
12. The compound of claim 1, wherein R.sup.5 and R.sup.6 are
independently selected from the group consisting of H, halide,
C.sub.1-3 alkyl, --X(C.sub.1-3 alkyl), --X(C.sub.1-3 haloalkyl),
--(C.sub.1-3 alkyl)OH, and C.sub.1-3 haloalkyl, or alternatively
R.sup.5 and R.sup.6 together with the atom to which they are
attached form a three to four membered carbocyclic ring optionally
substituted with one or more halide, or a four membered
heterocyclic ring.
13. The compound of claim 1, wherein R.sup.5 and R.sup.6 are H.
14. The compound of claim 1, wherein R.sup.5 is H and R.sup.6 is
selected from the group consisting of halide, CN, C.sub.1-3 alkyl,
--X(C.sub.1-3 alkyl), --X(C.sub.1-3 haloalkyl), --(C.sub.1-3
alkyl)CN, --(C.sub.1-3 alkyl)OH, and C.sub.1-3 haloalkyl.
15. The compound of claim 14, wherein R.sup.6 is selected from the
group consisting of F, CH.sub.3, CH.sub.2F, CHF.sub.2, CN,
OCH.sub.3, SCH.sub.3, OCH.sub.2F, SCH.sub.2F, OCHF.sub.2,
SCHF.sub.2, and CH.sub.2CN.
16. The compound of claim 1, wherein R.sup.5 and R.sup.6 are
independently selected from the group consisting of halide and
C.sub.1-3 alkyl.
17. The compound of claim 1, wherein R.sup.5 and R.sup.6 together
with the atom to which they are attached form a three to four
membered carbocyclic ring optionally substituted with one or more
halide, or a four membered heterocyclic ring.
18. The compound of claim 17, wherein R.sup.5 and R.sup.6 together
with the atom to which they are attached form a ring selected from
the group consisting of cyclobutyl, 3-fluoro-cyclobutyl,
2-oxetanyl, 3-oxetanyl, and cyclopropyl.
19. The compound of claim 1, wherein A is selected from the group
consisting of C--H, C--Cl, and N.
20. The compound of claim 1, having a structure selected from the
group consisting of: ##STR00058## ##STR00059## ##STR00060##
##STR00061## ##STR00062## ##STR00063## ##STR00064## ##STR00065## or
a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition, comprising a compound of claim 1
and a pharmaceutically acceptable carrier, diluent, excipient or
combination thereof.
22. A method of treating a bacterial infection, comprising
administering to a subject in need thereof a compound according to
claim 1.
23. The method of claim 22, wherein the bacteria is a gram negative
bacteria.
24. The method of claim 22, wherein the infection comprises a
bacteria that includes Pseudomonas aeruginosa, Pseudomonas
fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes,
Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia
cepacia group, Aeromonas hydrophilia, Escherichia coli, Citrobacter
freundii, Salmonella typhimurium, Salmonella typhi, Salmonella
paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella
flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter
aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia
marcescens, Francisella tularensis, Morganella morganii, Proteus
mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia
rettgeri, Providencia stuartii, Acinetobacter baumannii,
Acinetobacter calcoaceticus, Acinetobacter haemolyticus,
Acinetobacter anitratis, Yersinia enterocolitica, Yersinia pestis,
Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella
pertussis, Bordetella parapertussis, Bordetella bronchiseptica,
Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus
haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi,
Pasteurella multocida, Pasteurella haemolytica, Branhamella
catarrhalis, Helicobacter pylori, Campylobacter fetus,
Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi,
Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila,
Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria
meningitidis, Kingella, Moraxella, Gardnerella vaginalis,
Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A
homology group, Bacteroides vulgatus, Bacteroides ovalus,
Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides
eggerthii, Bacteroides splanchnicus, Clostridium difficile,
Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium
intracellulare, Mycobacterium leprae, Corynebacterium diphtherias,
Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus
agalactiae, Streptococcus pyogenes, Enterococcus faecalis,
Enterococcus faecium, Staphylococcus aureus, Staphylococcus
epidermidis, Staphylococcus saprophyticus, Staphylococcus
intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus
haemolyticus, Staphylococcus hominis, or Staphylococcus
saccharolyticus.
25. The method of claim 22, wherein the infection comprises a
bacteria that includes Pseudomonas aeruginosa, Pseudomonas
fluorescens, Stenotrophomonas maltophilia, Escherichia coli,
Citrobacter freundii, Salmonella typhimurium, Salmonella typhi,
Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae,
Shigella flexneri, Shigella sonnei, Enterobacter cloacae,
Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca,
Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter
haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia
pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae,
Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus
parahaemolyticus, Helicobacter pylori, Campylobacter fetus,
Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio
parahaemolyticus, Legionella pneumophila, Listeria monocytogenes,
Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella,
Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus,
Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides
eggerthii, or Bacteroides splanchnicus.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to the fields of chemistry and
medicine. More particularly, the present invention relates to
monobactam compounds that are useful for the treatment of bacterial
infections, especially Gram-negative infections. The invention also
relates to methods of using such compounds in the treatment of
bacterial infections and to pharmaceutical compositions and
pharmaceutical combinations containing such compounds.
[0003] 2. Description of the Related Art
[0004] Antibiotics have been effective tools in the treatment of
infectious diseases during the last half-century. From the
development of antibiotic therapy to the late 1980s there was
almost complete control over bacterial infections in developed
countries. However, in response to the pressure of antibiotic
usage, multiple resistance mechanisms have become widespread and
are threatening the clinical utility of antibacterial therapy. The
increase in antibiotic resistant strains has been particularly
common in major hospitals and care centers. The consequences of the
increase in resistant strains include higher morbidity and
mortality, longer patient hospitalization, and an increase in
treatment costs.
[0005] .beta.-Lactam antibiotics have been widely used for the
treatment of bacterial infections both in hospitals and in the
general public. There are several classes of .beta.-lactam
antibiotics that have found clinical application; these include the
penicillins, cephalosporins, cephamycins, carbacephems, oxacephems,
carbapenems and monobactams.
[0006] The efficiency of all of these classes to cure bacterial
infections has been impaired by the appearance of bacteria that are
resistant towards the antibiotics. The prevalent cause of this
resistance in Gram-negative bacteria is the expression by the
bacteria of enzymes known as .beta.-lactamases that are able to
hydrolyse the .beta.-lactam antibiotics rendering them inactive.
Bacteria are able to produce a variety of .beta.-lactamases,
including penicillinases, cephalo sporinases, cephamycinases,
carbapenemases, monobactamases, broad-spectrum .beta.-lactamases
and extended-spectrum .beta.-lactamases.
[0007] Monocyclic .beta.-lactam (monobactam) antibiotics inhibit
mucopeptide synthesis in the bacterial cell wall, thereby blocking
peptidoglycan crosslinking. They have a very high affinity for
penicillin-binding protein-3 (PBP-3) and mild affinity for PBP-1a
[Antimicrobial Agents and Chemotherapy (1983), 23(1), 98-104].
Monobactams have strong activity against susceptible gram-negative
bacteria, including Pseudomonas aeruginosa. Monobactams are known
to be effective against a wide range of bacteria including
Citrobacter, Enterobacter, E. coli, Haemophilus, Klebsiella,
Proteus, and Serratia species (Mosby's Drug Consult 2006 [16 ed.].
Mosby, Inc.)
[0008] Monocyclic .beta.-lactam antibacterials received
considerable attention [Chemotherapy (1987), 33(3), 165-171; Mayo
Clinic proceedings (1991), 66(11), 1152-1157; Lindner, K. R.,
Bonner, D. P., & Koster, W. H. (2000). Monobactams. Kirk-Othmer
Encyclopedia of Chemical Technology. John Wiley & Sons, Inc.]
largely due to their specific resistance profiles against bacterial
.beta.-lactamase enzymes. For example, aztreonam and carumonam, two
such antibiotics currently in use as antibacterials, show intrinsic
resistance toward class B .beta.-lactamases [Journal of Medical
Microbiology (2008), 57(8), 974-979; Journal of Chemotherapy
(2011), 23(5), 263-265] (zinc containing metalloenzymes). Activity
against the broad spectrum of gram negative bacteria is a desirable
characteristic of a modern .beta.-lactam antibiotics and it is
largely determined by the susceptibility of the .beta.-lactam core
to the enzymatic hydrolysis by a variety of bacterial
.beta.-lactamases. Thus, there is a need for new .beta.-lactam
antibiotics resistant to .beta.-lactamases.
SUMMARY OF THE INVENTION
[0009] The present invention relates to antimicrobial agents. Some
embodiments include compounds, compositions, pharmaceutical
compositions, use and preparation thereof. In particular, some
embodiments, relate to monocyclic .beta.-lactam compounds.
[0010] One embodiment disclosed herein includes a compound having
the structure of Formula I:
##STR00001##
[0011] In some embodiments of Formula (I):
[0012] R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, halide, CN, C.sub.1-3 alkyl, --X(C.sub.1-3
alkyl), --(C.sub.1-3 alkyl)OH, --(C.sub.1-3 alkyl)CN and C.sub.1-3
haloalkyl, or alternatively R.sup.1 and R.sup.2 together with the
atom to which they are attached form a three to four membered
carbocyclic ring optionally substituted with one or more halide, or
a four membered heterocyclic ring;
[0013] R.sup.3 and R.sup.4 are independently selected from the
group consisting of halide, CN, C.sub.1-3 alkyl, --X(C.sub.1-3
alkyl), --X(C.sub.1-3 haloalkyl), --(C.sub.1-3 alkyl)OH,
--(C.sub.1-3 alkyl)CN and C.sub.1-3 haloalkyl, or alternatively
R.sup.3 and R.sup.4 together with the atom to which they are
attached form a three to four membered carbocyclic ring optionally
substituted with one or more halide, or a four membered
heterocyclic ring;
[0014] R.sup.5 and R.sup.6 are independently selected from the
group consisting of H, halide, CN, C.sub.1-3 alkyl, --X(C.sub.1-3
alkyl), --X(C.sub.1-3 haloalkyl), --(C.sub.1-3 alkyl)OH,
--(C.sub.1-3 alkyl)CN and C.sub.1-3 haloalkyl, or alternatively
R.sup.5 and R.sup.6 together with the atom to which they are
attached form a three to four membered carbocyclic ring optionally
substituted with one or more halide, or a four membered
heterocyclic ring;
[0015] A is selected from the group consisting of C--H, C-halide,
and N; and
[0016] each X is independently selected from O or S.
[0017] In addition to the foregoing, some embodiments include a
pharmaceutical composition comprising a therapeutically effective
amount of any one of the foregoing compounds and a pharmaceutically
acceptable carrier, diluent, excipient or combination thereof.
[0018] In addition to the foregoing, some embodiments include any
one of the foregoing compounds or compositions for the treatment of
a bacterial infection.
[0019] In addition to the foregoing, some embodiments include
methods for treating a bacterial infection comprising administering
to a subject in need thereof, an effective amount of any one of the
foregoing compounds or compositions.
[0020] Some embodiments further comprise administering an
additional medicament.
[0021] In addition to the foregoing, some embodiments include the
use of any one of the foregoing compounds or compositions in the
preparation of a medicament for the treatment of a bacterial
infection.
[0022] In some embodiments, the use of any one of the foregoing
compounds or compositions, further comprises the use of an
additional medicament for treating or preventing a bacterial
infection.
[0023] In some embodiments, the additional medicament includes a
.beta.-lactamase inhibitor, efflux pump inhibitor, antifungal
agent, an antiviral agent, an anti-inflammatory agent or an
anti-allergic agent.
[0024] In some embodiments, the subject is a mammal.
[0025] In some embodiments, the mammal is a human.
[0026] In some embodiments, the infection comprises a bacteria that
includes Pseudomonas aeruginosa, Pseudomonas fluorescens,
Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas
putida, Stenotrophomonas maltophilia, Burkholderia cepacia group,
Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii,
Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi,
Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri,
Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes,
Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens,
Francisella tularensis, Morganella morganii, Proteus mirabilis,
Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri,
Providencia stuartii, Acinetobacter baumannii, Acinetobacter
calcoaceticus, Acinetobacter haemolyticus, Acinetobacter anitratis,
Yersinia enterocolitica, Yersinia pestis, Yersinia
pseudotuberculosis, Yersinia intermedia, Bordetella pertussis,
Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus
influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus,
Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella
multocida, Pasteurella haemolytica, Branhamella catarrhalis,
Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni,
Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio
parahaemolyticus, Legionella pneumophila, Listeria monocytogenes,
Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella,
Gardnerella vaginalis, Bacteroides fragilis, Bacteroides
distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus,
Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides
uniformis, Bacteroides eggerthii, Bacteroides splanchnicus,
Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium
avium, Mycobacterium intracellulare, Mycobacterium leprae,
Corynebacterium diphtherias, Corynebacterium ulcerans,
Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus
pyogenes, Enterococcus faecalis, Enterococcus faecium,
Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus
saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus
subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis,
or Staphylococcus saccharolyticus.
[0027] In some embodiments, the infection comprises a bacteria that
includes Pseudomonas aeruginosa, Pseudomonas fluorescens,
Stenotrophomonas maltophilia, Escherichia coli, Citrobacter
freundii, Salmonella typhimurium, Salmonella typhi, Salmonella
paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella
flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter
aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia
marcescens, Acinetobacter calcoaceticus, Acinetobacter
haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia
pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae,
Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus
parahaemolyticus, Helicobacter pylori, Campylobacter fetus,
Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio
parahaemolyticus, Legionella pneumophila, Listeria monocytogenes,
Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella,
Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus,
Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides
eggerthii, or Bacteroides splanchnicus.
[0028] Some embodiments of the present invention include methods to
prepare a compound of general Formula (I).
[0029] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the invention, as
claimed.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The present invention relates to antimicrobial agents and
potentiators thereof. Some embodiments include compounds,
compositions, pharmaceutical compositions, uses thereof, including
methods of preparation, and methods of treatment. In particular,
the present invention relates to monocyclic .beta.-lactam
compounds. Some embodiments include compounds of Formula (I):
##STR00002##
or pharmaceutically acceptable salts thereof.
[0031] In some embodiments, R.sup.1 and R.sup.2 are independently
selected from the group consisting of H, halide, CN, C.sub.1-3
alkyl, --(C.sub.1-3 alkyl)CN, --(C.sub.1-3 alkyl)OH, and C.sub.1-3
haloalkyl, or alternatively R.sup.1 and R.sup.2 together with the
atom to which they are attached form a three to four membered
carbocyclic ring optionally substituted with one or more halide, or
a four membered heterocyclic ring.
[0032] In some embodiments, R.sup.1 and R.sup.2 are H.
[0033] In some embodiments, R.sup.1 and R.sup.2 are independently
selected from the group consisting of H, halide, CN, C.sub.1-3
alkyl, --X(C.sub.1-3 alkyl), --(C.sub.1-3 alkyl)OH and
haloalkyl.
[0034] In some embodiments, R.sup.1 is H and R.sup.2 is selected
from the group consisting of halide, CN, C.sub.1-3 alkyl,
--(C.sub.1-3 alkyl)CN, --(C.sub.1-3 alkyl)OH, and C.sub.1-3
haloalkyl. In some such embodiments, R.sup.2 is selected from the
group consisting of CN, CH.sub.3, CH.sub.2OH, CH.sub.2CN and
CH.sub.2F.
[0035] In some embodiments, R.sup.1 and R.sup.2 are independently
selected from the group consisting of halide and C.sub.1-3
alkyl.
[0036] In some embodiments, R.sup.1 and R.sup.2 together with the
atom to which they are attached form a three to four membered
carbocyclic ring optionally substituted with one or more halide, or
a four membered heterocyclic ring. In some such embodiments,
R.sup.1 and R.sup.2 together with the atom to which they are
attached form a ring selected from the group consisting of
cyclobutyl, 3-fluoro-cyclobutyl, 2-oxetanyl, and 3-oxetanyl.
[0037] In some embodiments, R.sup.3 and R.sup.4 are independently
selected from the group consisting of halide, CN, C.sub.1-3 alkyl,
--X(C.sub.1-3 alkyl), --X(C.sub.1-3 haloalkyl), --(C.sub.1-3
alkyl)OH and haloalkyl.
[0038] In some embodiments, R.sup.3 and R.sup.4 are independently
selected from the group consisting of C.sub.1-3 alkyl and
--(C.sub.1-3 alkyl)OH.
[0039] In some embodiments, R.sup.3 and R.sup.4 are independently
selected from the group consisting F, CH.sub.3, CH.sub.2F,
CHF.sub.2, CN, OCH.sub.3, SCH.sub.3, OCH.sub.2F, SCH.sub.2F,
OCHF.sub.2, SCHF.sub.2, and CH.sub.2CN.
[0040] In some embodiments, R.sup.3 and R.sup.4, R.sup.3 and
R.sup.4 are independently selected from the group consisting F,
CH.sub.3, CH.sub.2F, CHF.sub.2, CN, OCH.sub.3, SCH.sub.3,
OCH.sub.2F, SCH.sub.2F, OCHF.sub.2, SCHF.sub.2, and CH.sub.2CN. In
some such embodiments, R.sup.3 and R.sup.4 together with the atom
to which they are attached form a ring selected from the group
consisting of cyclobutyl, 3-fluoro-cyclobutyl, 2-oxetanyl,
3-oxetanyl, and cyclopropyl.
[0041] In some embodiments, R.sup.5 and R.sup.6 are independently
selected from the group consisting of H, halide, C.sub.1-3 alkyl,
--X(C.sub.1-3 alkyl), --X(C.sub.1-3 haloalkyl), --(C.sub.1-3
alkyl)OH, and C.sub.1-3 haloalkyl, or alternatively R.sup.5 and
R.sup.6 together with the atom to which they are attached form a
three to four membered carbocyclic ring optionally substituted with
one or more halide, or a four membered heterocyclic ring.
[0042] In some embodiments, R.sup.5 and R.sup.6 are H.
[0043] In some embodiments, R.sup.5 and R.sup.6 are independently
selected from the group consisting of H, halide, CN, C.sub.1-3
alkyl, --X(C.sub.1-3 alkyl), --X(C.sub.1-3 haloalkyl), --(C.sub.1-3
alkyl)OH and haloalkyl.
[0044] In some embodiments, R.sup.5 is H and R.sup.6 is selected
from the group consisting of halide, CN, C.sub.1-3 alkyl,
--X(C.sub.1-3 alkyl), --X(C.sub.1-3 haloalkyl), --(C.sub.1-3
alkyl)CN, --(C.sub.1-3 alkyl)OH, and C.sub.1-3 haloalkyl. In some
such embodiments, R.sup.6 is selected from the group consisting of
F, CH.sub.3, CH.sub.2F, CHF.sub.2, CN, OCH.sub.3, SCH.sub.3,
OCH.sub.2F, SCH.sub.2F, OCHF.sub.2, SCHF.sub.2, and CH.sub.2CN.
[0045] In some embodiments, R.sup.5 and R.sup.6 are independently
selected from the group consisting of halide and C.sub.1-3
alkyl.
[0046] In some embodiments, R.sup.5 and R.sup.6 together with the
atom to which they are attached form a three to four membered
carbocyclic ring optionally substituted with one or more halide, or
a four membered heterocyclic ring. In some such embodiments,
R.sup.5 and R.sup.6 together with the atom to which they are
attached form a ring selected from the group consisting of
cyclobutyl, 3-fluoro-cyclobutyl, 2-oxetanyl, 3-oxetanyl, and
cyclopropyl
[0047] In some embodiments, A is selected from the group consisting
of C--H, C-halide, and N. In some such embodiments, A is selected
from the group consisting of C--H, C--Cl, and N.
[0048] In some embodiments, each X is independently selected from O
or S.
[0049] In some embodiments, R.sup.1 and R.sup.2 are independently
selected from the group consisting of H, --CH.sub.3, CN,
--CH.sub.2OH, --CH.sub.2F, --CHF.sub.2 and F.
[0050] In some embodiments, R.sup.1 and R.sup.2 are linked to form
a ring which selected from the group consisting of:
##STR00003##
[0051] In some embodiments, R.sup.3 and R.sup.4 are independently
selected from the group consisting of --CH.sub.3, CN, --CH.sub.2OH,
--CH.sub.2F, --CHF.sub.2, --OCH.sub.3, SCH.sub.3, --OCH.sub.2F,
--SCH.sub.2F, --OCHF.sub.2, --SCHF.sub.2, and F.
[0052] In some embodiments, R.sup.3 and R.sup.4 are linked to form
a ring which selected from the group consisting of:
##STR00004##
[0053] In some embodiments, R.sup.5 and R.sup.6 are independently
selected from the group consisting of H, --CH.sub.3, CN,
--CH.sub.2OH, --CH.sub.2F, --CHF.sub.2, --OCH.sub.3, SCH.sub.3,
--OCH.sub.2F, --SCH.sub.2F, --OCHF.sub.2, --SCHF.sub.2, and F.
[0054] In some embodiments, R.sup.5 and R.sup.6 are linked to form
a ring which selected from the group consisting of:
##STR00005##
[0055] Where the compounds disclosed herein have at least one
chiral center, they may exist as individual enantiomers and
diastereomers or as mixtures of such isomers, including racemates.
Separation of the individual isomers or selective synthesis of the
individual isomers is accomplished by application of various
methods which are well known to practitioners in the art. Unless
otherwise indicated, all such isomers and mixtures thereof are
included in the scope of the compounds disclosed herein.
Furthermore, compounds disclosed herein may exist in one or more
crystalline or amorphous forms. Unless otherwise indicated, all
such forms are included in the scope of the compounds disclosed
herein including any polymorphic forms. In addition, some of the
compounds disclosed herein may form solvates with water (i.e.,
hydrates) or common organic solvents. Unless otherwise indicated,
such solvates are included in the scope of the compounds disclosed
herein.
[0056] The skilled artisan will recognize that some structures
described herein may be resonance forms or tautomers of compounds
that may be fairly represented by other chemical structures, even
when kinetically; the artisan recognizes that such structures may
only represent a very small portion of a sample of such
compound(s). Such compounds are considered within the scope of the
structures depicted, though such resonance forms or tautomers are
not represented herein.
[0057] Isotopes may be present in the compounds described. Each
chemical element as represented in a compound structure may include
any isotope of said element. For example, in a compound structure a
hydrogen atom may be explicitly disclosed or understood to be
present in the compound. At any position of the compound that a
hydrogen atom may be present, the hydrogen atom can be any isotope
of hydrogen, including but not limited to hydrogen-1 (protium) and
hydrogen-2 (deuterium). Thus, reference herein to a compound
encompasses all potential isotopic forms unless the context clearly
dictates otherwise.
DEFINITIONS
[0058] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of ordinary skill in the art to which this disclosure belongs. All
patents, applications, published applications, and other
publications are incorporated by reference in their entirety. In
the event that there is a plurality of definitions for a term
herein, those in this section prevail unless stated otherwise.
[0059] "Solvate" refers to the compound formed by the interaction
of a solvent and a compound described herein or salt thereof.
Suitable solvates are pharmaceutically acceptable solvates
including hydrates.
[0060] The term "pharmaceutically acceptable salt" refers to salts
that retain the biological effectiveness and properties of a
compound and, which are not biologically or otherwise undesirable
for use in a pharmaceutical. In many cases, the compounds disclosed
herein are capable of forming acid and/or base salts by virtue of
the presence of amino and/or carboxyl groups or groups similar
thereto. Pharmaceutically acceptable acid addition salts can be
formed with inorganic acids and organic acids. Inorganic acids from
which salts can be derived include, for example, hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and
the like. Organic acids from which salts can be derived include,
for example, acetic acid, propionic acid, glycolic acid, pyruvic
acid, oxalic acid, maleic acid, malonic acid, succinic acid,
fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic
acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with
inorganic and organic bases. Inorganic bases from which salts can
be derived include, for example, sodium, potassium, lithium,
ammonium, calcium, magnesium, iron, zinc, copper, manganese,
aluminum, and the like; particularly preferred are the ammonium,
potassium, sodium, calcium and magnesium salts. Organic bases from
which salts can be derived include, for example, primary,
secondary, and tertiary amines, substituted amines including
naturally occurring substituted amines, cyclic amines, basic ion
exchange resins, and the like, specifically such as isopropylamine,
trimethylamine, diethylamine, triethylamine, tripropylamine, and
ethanolamine. Many such salts are known in the art, as described in
WO 87/05297, Johnston et al., published Sep. 11, 1987 (incorporated
by reference herein in its entirety).
[0061] As used herein, "C.sub.a to C.sub.b" or "C.sub.a-b" in which
"a" and "b" are integers refer to the number of carbon atoms in the
specified group. That is, the group can contain from "a" to "b",
inclusive, carbon atoms. Thus, for example, a "C.sub.1 to C.sub.4
alkyl" or "C.sub.1-4 alkyl" group refers to all alkyl groups having
from 1 to 4 carbons, that is, CH.sub.3--, CH.sub.3CH.sub.2--,
CH.sub.3CH.sub.2CH.sub.2--, (CH.sub.3).sub.2CH--,
CH.sub.3CH.sub.2CH.sub.2CH.sub.2--, CH.sub.3CH.sub.2CH(CH.sub.3)--
and (CH.sub.3).sub.3C--.
[0062] As used herein, "alkyl" means a branched, or straight chain
chemical group containing only carbon and hydrogen, such as methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,
tert-butyl, n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl. Alkyl
groups can be saturated or unsaturated (e.g., containing
--C.dbd.C-- or --C.ident.C-- subunits), at one or several
positions. Typically, alkyl groups will comprise 1 to 9 carbon
atoms, preferably 1 to 6, more preferably 1 to 4, and most
preferably 1 to 3 carbon atoms.
[0063] As used herein, "carbocyclyl" means a cyclic ring system
containing only carbon atoms in the ring system backbone, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl.
Carbocyclyls may include multiple fused rings. Carbocyclyls may
have any degree of saturation provided that at least one ring in
the ring system is not aromatic. Typically, carbocyclyl groups will
comprise 3 to 10 carbon atoms, preferably 3 to 4.
[0064] As used herein, "halo", "halide" or "halogen" is a chloro,
bromo, fluoro or iodo atom radical. Chloro, bromo and fluoro are
preferred halides. Most preferred halide is fluorine.
[0065] As used herein, "haloalkyl" means a hydrocarbon substituent,
which is a linear or branched alkyl, alkenyl or alkynyl substituted
with chloro, bromo, fluoro or iodo atom(s). Most preferred of these
are fluoroalkyls, wherein one or more of the hydrogen atoms have
been substituted by fluoro. Preferred haloalkyls are of 1 to about
3 carbons in length, more preferred haloalkyls are 1 to about 2
carbons, and most preferred are 1 carbon in length. The skilled
artisan will recognize then that as used herein, "haloalkylene"
means a diradical variant of haloalkyl, such diradicals may act as
spacers between radicals, other atoms, or between the parent ring
and another functional group.
[0066] As used herein, "carbocyclyl" means a non-aromatic cyclic
ring or ring system containing only carbon atoms in the ring system
backbone. When the carbocyclyl is a ring system, two or more rings
may be joined together in a fused, bridged or spiro-connected
fashion. Carbocyclyls may have any degree of saturation provided
that at least one ring in a ring system is not aromatic. Thus,
carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
The carbocyclyl group may have 3 to 20 carbon atoms, although the
present definition also covers the occurrence of the term
"carbocyclyl" where no numerical range is designated. The
carbocyclyl group may also be a medium size carbocyclyl having 3 to
10 carbon atoms. The carbocyclyl group could also be a carbocyclyl
having 3 to 6 carbon atoms. The carbocyclyl group may be designated
as "C.sub.3-6 carbocyclyl" or similar designations. Examples of
carbocyclyl rings include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,
2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and
spiro[4.4]nonanyl.
[0067] As used herein, "heterocyclyl" means a cyclic ring system
comprising at least one heteroatom in the ring system backbone.
Heterocyclyls may include multiple fused rings. Heterocyclyls may
have any degree of saturation provided that at least one ring in
the ring system is not aromatic. More preferred heterocycles are of
4-7 members. Most preferred heterocycles are 4 membered. In six
membered monocyclic heterocycles, the heteroatom(s) are selected
from one up to three of O, N or S, and wherein when the heterocycle
is five membered, preferably it has one or two heteroatoms selected
from O, N, or S. Examples of heterocyclyl include azirinyl,
aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl,
1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl,
dihydrocinnolinyl, dihydrobenzodioxinyl,
dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl,
dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl,
1,3-dioxolanyl, isoindolinyl, morpholinyl, thiomorpholinyl,
piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl,
tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl,
isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl,
pyrazolidinyl imidazolidinyl, thiomorpholinyl, oxetanyl, and
others.
[0068] When two R groups are said to form a ring (e.g., a
carbocyclyl or heterocyclyl ring) "together with the atom to which
they are attached," it is meant that the collective unit of the
atom and the two R groups are the recited ring. The ring is not
otherwise limited by the definition of each R group when taken
individually. For example, when the following substructure is
present:
##STR00006##
and R.sup.1 and R.sup.2 are defined as selected from the group
consisting of hydrogen and alkyl, or R.sup.1 and R.sup.2 together
with the nitrogen to which they are attached form a heterocycle, it
is meant that R.sup.1 and R.sup.2 can be selected from hydrogen or
alkyl, or alternatively, the substructure has structure:
##STR00007##
where ring A is a heterocycle ring containing the depicted
nitrogen.
[0069] The term "agent" or "test agent" includes any substance,
molecule, element, compound, entity, or a combination thereof. It
includes, but is not limited to, e.g., protein, polypeptide,
peptide or mimetic, small organic molecule, polysaccharide,
polynucleotide, and the like. It can be a natural product, a
synthetic compound, or a chemical compound, or a combination of two
or more substances. Unless otherwise specified, the terms "agent",
"substance", and "compound" are used interchangeably herein.
[0070] The term "administration" or "administering" refers to a
method of giving a dosage of a compound or pharmaceutical
composition to a vertebrate or invertebrate, including a mammal, a
bird, a fish, or an amphibian, where the method is, e.g., orally,
subcutaneously, intravenously, intranasally, topically,
transdermally, intraperitoneally, intramuscularly,
intrapulmonarilly, vaginally, rectally, ontologically,
neuro-otologically, intraocularly, subconjuctivally, via anterior
eye chamber injection, intravitreally, intraperitoneally,
intrathecally, intracystically, intrapleurally, via wound
irrigation, intrabuccally, intra-abdominally, intra-articularly,
intra-aurally, intrabronchially, intracapsularly, intrameningeally,
via inhalation, via endotracheal or endobronchial instillation, via
direct instillation into pulmonary cavities, intraspinally,
intrasynovially, intrathoracically, via thoracostomy irrigation,
epidurally, intratympanically, intracisternally, intravascularly,
intraventricularly, intraosseously, via irrigation of infected
bone, or via application as part of any admixture with a prosthetic
device. The preferred method of administration can vary depending
on various factors, e.g., the components of the pharmaceutical
composition, the site of the disease, the disease involved, and the
severity of the disease.
[0071] A "diagnostic" as used herein is a compound, method, system,
or device that assists in the identification and characterization
of a health or disease state. The diagnostic can be used in
standard assays as is known in the art.
[0072] The term "mammal" is used in its usual biological sense.
Thus, it specifically includes humans, cattle, horses, dogs, and
cats, but also includes many other species.
[0073] The term "microbial infection" refers to the invasion of the
host organism, whether the organism is a vertebrate, invertebrate,
fish, plant, bird, or mammal, by pathogenic microbes. This includes
the excessive growth of microbes that are normally present in or on
the body of a mammal or other organism. More generally, a microbial
infection can be any situation in which the presence of a microbial
population(s) is damaging to a host mammal. Thus, a mammal is
"suffering" from a microbial infection when excessive numbers of a
microbial population are present in or on a mammal's body, or when
the effects of the presence of a microbial population(s) is
damaging the cells or other tissue of a mammal. Specifically, this
description applies to a bacterial infection. Note that the
compounds of preferred embodiments are also useful in treating
microbial growth or contamination of cell cultures or other media,
or inanimate surfaces or objects, and nothing herein should limit
the preferred embodiments only to treatment of higher organisms,
except when explicitly so specified in the claims.
[0074] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" includes any and all
solvents, co-solvents, complexing agents, dispersion media,
coatings, antibacterial and antifungal agents, isotonic and
absorption delaying agents and the like which are not biologically
or otherwise undesirable. The use of such media and agents for
pharmaceutically active substances is well known in the art. Except
insofar as any conventional media or agent is incompatible with the
active ingredient, its use in the therapeutic compositions is
contemplated. Supplementary active ingredients can also be
incorporated into the compositions. In addition, various adjuvants
such as are commonly used in the art may be included. These and
other such compounds are described in the literature, e.g., in the
Merck Index, Merck & Company, Rahway, N.J. Considerations for
the inclusion of various components in pharmaceutical compositions
are described, e.g., in Gilman et al. (Eds.) (2010); Goodman and
Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The
McGraw-Hill Companies.
[0075] "Subject" as used herein, means a human or a non-human
mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig,
a goat, a non-human primate or a bird, e.g., a chicken, as well as
any other vertebrate or invertebrate.
[0076] Some embodiments include use of a therapeutically effective
amount or a pharmaceutically effective amount of a compound
disclosed herein. A "therapeutically effective amount" or
"pharmaceutically effective amount" of a compound as provided
herein is one which is sufficient to achieve the desired effect and
may vary according to the nature and severity of the disease
condition, and the potency of the compound. "Therapeutically
effective amount" is also intended to include one or more of the
compounds of Formula (I) in combination with one or more other
agents that are effective to treat a microbial infection and/or
conditions. The combination of compounds is preferably a
synergistic combination. Synergy, as described, for example, by
Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55,
occurs when the effect of the compounds when administered in
combination is greater than the additive effect of the compounds
when administered alone as a single agent. In general, a
synergistic effect is most clearly demonstrated at sub-optimal
concentrations of the compounds. It will be appreciated that
different concentrations may be employed for prophylaxis than for
treatment of an active disease. This amount can further depend upon
the patient's height, weight, sex, age and medical history.
[0077] A therapeutic effect relieves, to some extent, one or more
of the symptoms of the disease, and includes curing a disease.
"Curing" means that the symptoms of active disease are eliminated.
However, certain long-term or permanent effects of the disease may
exist even after a cure is obtained (such as extensive tissue
damage).
[0078] "Treat," "treatment," or "treating," as used herein refers
to administering a compound or pharmaceutical composition to a
subject for prophylactic and/or therapeutic purposes. The term
"therapeutic treatment" refers to administering treatment to a
patient already suffering from a disease thus causing a
therapeutically beneficial effect, such as ameliorating existing
symptoms, preventing additional symptoms, ameliorating or
preventing the underlying metabolic causes of symptoms, postponing
or preventing the further development of a disorder and/or reducing
the severity of symptoms that will or are expected to develop. The
term "prophylactic treatment" refers to treating a subject who does
not yet exhibit symptoms of a disease or condition, but who is
susceptible to, or otherwise at risk of, a particular disease or
condition, whereby the treatment reduces the likelihood that the
patient will develop the disease or condition.
Administration and Pharmaceutical Compositions
[0079] Some embodiments include pharmaceutical compositions
comprising: (a) a safe and therapeutically effective amount of a
compound provided herein, or a pharmaceutically acceptable salt
thereof; and (b) a pharmaceutically acceptable carrier, diluent,
excipient or combination thereof.
[0080] Administration of the compounds disclosed herein or the
pharmaceutically acceptable salts thereof can be via any of the
accepted modes of administration for agents that serve similar
utilities including, but not limited to, orally, subcutaneously,
intravenously, intranasally, topically, transdermally,
intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,
rectally, ontologically, neuro-otologically, intraocularly,
subconjuctivally, via anterior eye chamber injection,
intravitreally, intraperitoneally, intrathecally, intracystically,
intrapleurally, via wound irrigation, intrabuccally,
intra-abdominally, intra-articularly, intra-aurally,
intrabronchially, intracapsularly, intrameningeally, via
inhalation, via endotracheal or endobronchial instillation, via
direct instillation into pulmonary cavities, intraspinally,
intrasynovially, intrathoracically, via thoracostomy irrigation,
epidurally, intratympanically, intracisternally, intravascularly,
intraventricularly, intraosseously, via irrigation of infected
bone, or via application as part of any admixture with a prosthetic
devices. Oral and parenteral administrations are customary in
treating the indications.
[0081] Compounds provided herein intended for pharmaceutical use
may be administered as crystalline or amorphous products.
Pharmaceutically acceptable compositions may include solid,
semi-solid, liquid, solutions, colloidal, liposomes, emulsions,
suspensions, complexes, coacervates and aerosols. Dosage forms,
such as, e.g., tablets, capsules, powders, liquids, suspensions,
suppositories, aerosols, implants, controlled release or the like.
They may be obtained, for example, as solid plugs, powders, or
films by methods such as precipitation, crystallization, milling,
grinding, supercritical fluid processing, coacervation, complex
coacervation, encapsulation, emulsification, complexation, freeze
drying, spray drying, or evaporative drying. Microwave or radio
frequency drying may be used for this purpose. The compounds can
also be administered in sustained or controlled release dosage
forms, including depot injections, osmotic pumps, pills (tablets
and or capsules), transdermal (including electrotransport) patches,
implants and the like, for prolonged and/or timed, pulsed
administration at a predetermined rate.
[0082] The compounds can be administered either alone or more
typically in combination with a conventional pharmaceutical
carrier, excipient or the like. The term "excipient" is used herein
to describe any ingredient other than the compound(s) provided
herein. Pharmaceutically acceptable excipients include, but are not
limited to, ion exchangers, alumina, aluminum stearate, lecithin,
self-emulsifying drug delivery systems (SEDDS) such as
d-.alpha.-tocopherol polyethylene glycol 1000 succinate,
surfactants used in pharmaceutical dosage forms such as Tweens,
poloxamers or other similar polymeric delivery matrices, serum
proteins, such as human serum albumin, buffer substances such as
phosphates, tris, glycine, sorbic acid, potassium sorbate, partial
glyceride mixtures of saturated vegetable fatty acids, water, salts
or electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium-chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, cellulose-based substances, polyethylene glycol,
sodium carboxymethyl cellulose, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, and wool fat.
Cyclodextrins such as .alpha.-, .beta., and .gamma.-cyclodextrin,
or chemically modified derivatives such as
hydroxyalkylcyclodextrins, including 2- and
3-hydroxypropyl-b-cyclodextrins, or other solubilized derivatives
can also be advantageously used to enhance delivery of compounds
described herein. Dosage forms or compositions containing a
compound as described herein in the range of 0.005% to 100% with
the balance made up from non-toxic carrier may be prepared. The
contemplated compositions may contain 0.001%-100% active
ingredient, in one embodiment 0.1-95%, in another embodiment
75-85%, in a further embodiment 20-80%, Actual methods of preparing
such dosage forms are known, or will be apparent, to those skilled
in this art; for example, see Remington: The Science and Practice
of Pharmacy, 22.sup.nd Edition (Pharmaceutical Press, London, UK.
2012).
[0083] In one preferred embodiment, the compositions will take the
form of a unit dosage form such as a pill or tablet and thus the
composition may contain, along with the active ingredient, a
diluent such as lactose, sucrose, dicalcium phosphate, or the like;
a lubricant such as magnesium stearate or the like; and a binder
such as starch, gum acacia, polyvinylpyrrolidine, gelatin,
cellulose, cellulose derivatives or the like. In another solid
dosage form, a powder, marume, solution or suspension (e.g., in
propylene carbonate, vegetable oils, PEG's, poloxamer 124 or
triglycerides) is encapsulated in a capsule (gelatin or cellulose
base capsule). Unit dosage forms in which the two active
ingredients are physically separated are also contemplated; e.g.,
capsules with granules (or tablets in a capsule) of each drug;
two-layer tablets; two-compartment gel caps, etc. Enteric coated or
delayed release oral dosage forms are also contemplated.
[0084] Liquid pharmaceutically administrable compositions can, for
example, be prepared by dissolving, dispersing, etc. an active
compound as defined above and optional pharmaceutical adjuvants in
a carrier (e.g., water, saline, aqueous dextrose, glycerol,
glycols, ethanol or the like) to form a solution, colloid,
liposome, emulsion, complexes, coacervate or suspension. If
desired, the pharmaceutical composition can also contain minor
amounts of nontoxic auxiliary substances such as wetting agents,
emulsifying agents, co-solvents, solubilizing agents, pH buffering
agents and the like (e.g., sodium acetate, sodium citrate,
cyclodextrine derivatives, sorbitan monolaurate, triethanolamine
acetate, triethanolamine oleate, and the like).
[0085] In some embodiments, the unit dosage of compounds of Formula
(I) is 0.25 mg/Kg to 120 mg/Kg in humans.
[0086] In some embodiments, the unit dosage of compounds of Formula
(I) is 0.50 mg/Kg to 70 mg/Kg in humans.
[0087] In some embodiments, the unit dosage of compounds of Formula
(I) is 1.0 mg/Kg to 50 mg/Kg in humans.
[0088] In some embodiments, the unit dosage of compounds of Formula
(I) is 1.50 mg/Kg to 10 mg/Kg in humans.
[0089] In some embodiments, the compositions are provided in unit
dosage forms suitable for single administration of a precise
dose.
[0090] In some embodiments, the compositions are provided in unit
dosage forms suitable for twice a day administration of a precise
dose.
[0091] In some embodiments, the compositions are provided in unit
dosage forms suitable for three times a day administration of a
precise dose.
[0092] Injectables can be prepared in conventional forms, either as
liquid solutions, colloid, liposomes, complexes, coacervate or
suspensions, as emulsions, or in solid forms suitable for
reconstitution in liquid prior to injection. Suitable excipients
may be included to achieve the desired pH, including but not
limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric
acid. In various embodiments, the pH of the final composition
ranges from 2 to 8, or preferably from 4 to 7. Antioxidant
excipients may include sodium bisulfite, acetone sodium bisulfite,
sodium formaldehyde, sulfoxylate, thiourea, and EDTA. Other
non-limiting examples of suitable excipients found in the final
intravenous composition may include sodium or potassium phosphates,
citric acid, tartaric acid, gelatin, and carbohydrates such as
dextrose, mannitol, and dextran. Further acceptable excipients are
described in Powell, et al., Compendium of Excipients for
Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311
and Nema et al., Excipients and Their Role in Approved Injectable
Products: Current Usage and Future Directions, PDA J Pharm Sci and
Tech 2011, 65 287-332, both of which are incorporated herein by
reference in their entirety. Antimicrobial agents may also be
included to achieve a bacteriostatic or fungistatic solution,
including but not limited to phenylmercuric nitrate, thimerosal,
benzethonium chloride, benzalkonium chloride, phenol, cresol, and
chlorobutanol.
[0093] The compositions for intravenous administration may be
provided to caregivers in the form of one more solids that are
reconstituted with a suitable diluent such as sterile water, saline
or dextrose in water shortly prior to administration. In other
embodiments, the compositions are provided in solution ready to
administer parenterally. In still other embodiments, the
compositions are provided in a solution that is further diluted
prior to administration. In embodiments that include administering
a combination of a compound described herein and another agent, the
combination may be provided to caregivers as a mixture, or the
caregivers may mix the two agents prior to administration, or the
two agents may be administered separately.
[0094] The percentage of active compound contained in such
parenteral compositions is highly dependent on the specific nature
thereof, as well as the activity of the compound and the needs of
the subject. However, percentages of active ingredient of 0.01% to
10% in solution are employable, and could be higher if the
composition is a solid or suspension, which could be subsequently
diluted to the above percentages.
[0095] In some embodiments, the composition will comprise 0.1-10%
of the active agent in solution.
[0096] In some embodiments, the composition will comprise 0.1-5% of
the active agent in solution.
[0097] In some embodiments, the composition will comprise 0.1-4% of
the active agent in solution.
[0098] In some embodiments, the composition will comprise 0.15-3%
of the active agent in solution.
[0099] In some embodiments, the composition will comprise 0.2-2% of
the active agent in solution.
[0100] In some embodiments, the compositions are provided in dosage
forms suitable for continuous dosage by intravenous infusion over a
period of 1-96 hours.
[0101] In some embodiments, the compositions are provided in dosage
forms suitable for continuous dosage by intravenous infusion over a
period of 1-72 hours.
[0102] In some embodiments, the compositions are provided in dosage
forms suitable for continuous dosage by intravenous infusion over a
period of 1-48 hours.
[0103] In some embodiments, the compositions are provided in dosage
forms suitable for continuous dosage by intravenous infusion over a
period of 1-24 hours.
[0104] In some embodiments, the compositions are provided in dosage
forms suitable for continuous dosage by intravenous infusion over a
period of 1-12 hours.
[0105] In some embodiments, the compositions are provided in dosage
forms suitable for continuous dosage by intravenous infusion over a
period of 1-6 hours.
[0106] In some embodiments, these compositions can be administered
by intravenous infusion to humans at doses of 5 mg/m.sup.2 to 300
mg/m.sup.2.
[0107] In some embodiments, these compositions can be administered
by intravenous infusion to humans at doses of 5 mg/m.sup.2 to 200
mg/m.sup.2.
[0108] In some embodiments, these compositions can be administered
by intravenous infusion to humans at doses of 5 mg/m.sup.2 to 100
mg/m.sup.2.
[0109] In some embodiments, these compositions can be administered
by intravenous infusion to humans at doses of 10 mg/m.sup.2 to 50
mg/m.sup.2.
[0110] In some embodiments, these compositions can be administered
by intravenous infusion to humans at doses of 50 mg/m.sup.2 to 200
mg/m.sup.2.
[0111] In some embodiments, these compositions can be administered
by intravenous infusion to humans at doses of 75 mg/m.sup.2 to 175
mg/m.sup.2.
[0112] In some embodiments, these compositions can be administered
by intravenous infusion to humans at doses of 100 mg/m.sup.2 to 150
mg/m.sup.2.
[0113] It is to be noted that concentrations and dosage values may
also vary depending on the specific compound and the severity of
the condition to be alleviated. It is to be further understood that
for any particular patient, specific dosage regimens should be
adjusted over time according to the individual need and the
professional judgment of the person administering or supervising
the administration of the compositions, and that the concentration
ranges set forth herein are exemplary only and are not intended to
limit the scope or practice of the claimed compositions.
[0114] In one preferred embodiment, the compositions can be
administered to the respiratory tract (including nasal and
pulmonary) e.g., through a nebulizer, metered-dose inhalers,
atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid
instillation or other suitable device or technique.
[0115] In some embodiments, aerosols intended for delivery to the
nasal mucosa are provided for inhalation through the nose. For
optimal delivery to the nasal cavities, inhaled particle sizes of
about 5 to about 100 microns are useful, with particle sizes of
about 10 to about 60 microns being preferred. For nasal delivery, a
larger inhaled particle size is desired to maximize impaction on
the nasal mucosa and to minimize or prevent pulmonary deposition of
the administered formulation. In some embodiments, aerosols
intended for delivery to the lung are provided for inhalation
through the nose or the mouth. For optimal delivery to the lung,
inhaled aerodynamic particle sizes of about less than 10 .mu.m are
useful, with an aerodynamic particle size of about 1 to about 10
microns being preferred. Inhaled particles may be defined as liquid
droplets containing dissolved drug, liquid droplets containing
suspended drug particles (in cases where the drug is insoluble in
the suspending medium), dry particles of pure drug substance, drug
substance incorporated with excipients, liposomes, emulsions,
colloidal systems, coacervates, aggregates of drug nanoparticles,
or dry particles of a diluent which contain embedded drug
nanoparticles.
[0116] In some embodiments, compounds of Formula (I) disclosed
herein intended for respiratory delivery (either systemic or local)
can be administered as aqueous formulations, as non-aqueous
solutions or suspensions, as suspensions or solutions in
halogenated hydrocarbon propellants with or without alcohol, as a
colloidal system, as emulsions, coacervates or as dry powders.
Aqueous formulations may be aerosolized by liquid nebulizers
employing either hydraulic or ultrasonic atomization or by modified
micropump systems (like the soft mist inhalers, the Aerodose or the
AERx.RTM. systems). Propellant-based systems may use suitable
pressurized metered-dose inhalers (pMDIs). Dry powders may use dry
powder inhaler devices (DPIs), which are capable of dispersing the
drug substance effectively. A desired particle size and
distribution may be obtained by choosing an appropriate device.
[0117] In some embodiments, the compositions of Formula (I)
disclosed herein can be administered to the ear by various methods.
For example, a round window catheter (e.g., U.S. Pat. Nos.
6,440,102 and 6,648,873) can be used.
[0118] Alternatively, formulations can be incorporated into a wick
for use between the outer and middle ear (e.g., U.S. Pat. No.
6,120,484) or absorbed to collagen sponge or other solid support
(e.g., U.S. Pat. No. 4,164,559).
[0119] If desired, formulations of the invention can be
incorporated into a gel formulation (e.g., U.S. Pat. Nos. 4,474,752
and 6,911,211).
[0120] In some embodiments, compounds of Formula (I) disclosed
herein intended for delivery to the ear can be administered via an
implanted pump and delivery system through a needle directly into
the middle or inner ear (cochlea) or through a cochlear implant
stylet electrode channel or alternative prepared drug delivery
channel such as but not limited to a needle through temporal bone
into the cochlea.
[0121] Other options include delivery via a pump through a thin
film coated onto a multichannel electrode or electrode with a
specially imbedded drug delivery channel (pathways) carved into the
thin film for this purpose. In other embodiments the acidic or
basic solid gacyclidine can be delivered from the reservoir of an
external or internal implanted pumping system.
[0122] Formulations of the invention also can be administered to
the ear by intratympanic injection into the middle ear, inner ear,
or cochlea (e.g., U.S. Pat. No. 6,377,849 and Ser. No.
11/337,815).
[0123] Intratympanic injection of therapeutic agents is the
technique of injecting a therapeutic agent behind the tympanic
membrane into the middle and/or inner ear. In one embodiment, the
formulations described herein are administered directly onto the
round window membrane via transtympanic injection. In another
embodiment, the ion channel modulating agent auris-acceptable
formulations described herein are administered onto the round
window membrane via a non-transtympanic approach to the inner ear.
In additional embodiments, the formulation described herein is
administered onto the round window membrane via a surgical approach
to the round window membrane comprising modification of the crista
fenestrae cochleae.
[0124] In some embodiments, the compounds of Formula (I) are
formulated in rectal compositions such as enemas, rectal gels,
rectal foams, rectal aerosols, suppositories, jelly suppositories,
or retention enemas, containing conventional suppository bases such
as cocoa butter or other glycerides, as well as synthetic polymers
such as polyvinylpyrrolidone, PEG (like PEG ointments), and the
like.
[0125] Suppositories for rectal administration of the drug (either
as a solution, colloid, suspension or a complex) can be prepared by
mixing the drug with a suitable non-irritating excipient that is
solid at ordinary temperatures but liquid at the rectal temperature
and will therefore melt or erode/dissolve in the rectum and release
the drug. Such materials include cocoa butter, glycerinated
gelatin, hydrogenated vegetable oils, poloxamers, mixtures of
polyethylene glycols of various molecular weights and fatty acid
esters of polyethylene glycol. In suppository forms of the
compositions, a low-melting wax such as, but not limited to, a
mixture of fatty acid glycerides, optionally in combination with
cocoa butter is first melted.
[0126] A liquid composition, which is formulated for topical
ophthalmic use, is formulated such that it can be administered
topically to the eye. The comfort should be maximized as much as
possible, although sometimes formulation considerations (e.g. drug
stability) may necessitate less than optimal comfort. In the case
that comfort cannot be maximized, the liquid should be formulated
such that the liquid is tolerable to the patient for topical
ophthalmic use. Additionally, an ophthalmically acceptable liquid
should either be packaged for single use, or contain a preservative
to prevent contamination over multiple uses.
[0127] For ophthalmic application, solutions or medicaments are
often prepared using a physiological saline solution as a major
vehicle. Ophthalmic solutions should preferably be maintained at a
comfortable pH with an appropriate buffer system. The formulations
may also contain conventional, pharmaceutically acceptable
preservatives, stabilizers and surfactants.
[0128] Preservatives that may be used in the pharmaceutical
compositions disclosed herein include, but are not limited to,
benzalkonium chloride, PHMB, chlorobutanol, thimerosal,
phenylmercuric, acetate and phenylmercuric nitrate. A useful
surfactant is, for example, Tween 80. Likewise, various useful
vehicles may be used in the ophthalmic preparations disclosed
herein. These vehicles include, but are not limited to, polyvinyl
alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers,
carboxymethyl cellulose, hydroxyethyl cellulose and purified
water.
[0129] Tonicity adjustors may be added as needed or convenient.
They include, but are not limited to, salts, particularly sodium
chloride, potassium chloride, mannitol and glycerin, or any other
suitable ophthalmically acceptable tonicity adjustor.
[0130] Various buffers and means for adjusting pH may be used so
long as the resulting preparation is ophthalmically acceptable. For
many compositions, the pH will be between 4 and 9. Accordingly,
buffers include acetate buffers, citrate buffers, phosphate buffers
and borate buffers. Acids or bases may be used to adjust the pH of
these formulations as needed.
[0131] In a similar vein, an ophthalmically acceptable antioxidant
includes, but is not limited to, sodium metabisulfite, sodium
thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated
hydroxytoluene.
[0132] Other excipient components, which may be included in the
ophthalmic preparations, are chelating agents. A useful chelating
agent is edetate disodium, although other chelating agents may also
be used in place or in conjunction with it.
[0133] For topical use, creams, ointments, gels, solutions or
suspensions, etc., containing the compound disclosed herein are
employed. Topical formulations may generally be comprised of a
pharmaceutical carrier, co-solvent, emulsifier, penetration
enhancer, preservative system, and emollient.
[0134] Solid compositions can be provided in various different
types of dosage forms, depending on the physicochemical properties
of the drug, the desired dissolution rate, cost considerations, and
other criteria. In one of the embodiments, the solid composition is
a single unit. This implies that one unit dose of the drug is
comprised in a single, physically shaped solid form or article. In
other words, the solid composition is coherent, which is in
contrast to a multiple unit dosage form, in which the units are
incoherent.
[0135] Examples of single units which may be used as dosage forms
for the solid composition include tablets, such as compressed
tablets, film-like units, foil-like units, wafers, lyophilized
matrix units, and the like. In a preferred embodiment, the solid
composition is a highly porous lyophilized form. Such
lyophilizates, sometimes also called wafers or lyophilized tablets,
are particularly useful for their rapid disintegration, which also
enables the rapid dissolution of the active compound.
[0136] On the other hand, for some applications the solid
composition may also be formed as a multiple unit dosage form as
defined above. Examples of multiple units are powders, granules,
microparticles, pellets, mini-tablets, beads, lyophilized powders,
and the like. In one embodiment, the solid composition is a
lyophilized powder. Such a dispersed lyophilized system comprises a
multitude of powder particles, and due to the lyophilization
process used in the formation of the powder, each particle has an
irregular, porous microstructure through which the powder is
capable of absorbing water very rapidly, resulting in quick
dissolution. Effervescent compositions are also contemplated to aid
the quick dispersion and absorption of the compound.
[0137] Another type of multiparticulate system which is also
capable of achieving rapid drug dissolution is that of powders,
granules, or pellets from water-soluble excipients which are coated
with the drug, so that the drug is located at the outer surface of
the individual particles. In this type of system, the water-soluble
low molecular weight excipient is useful for preparing the cores of
such coated particles, which can be subsequently coated with a
coating composition comprising the drug and, preferably, one or
more additional excipients, such as a binder, a pore former, a
saccharide, a sugar alcohol, a film-forming polymer, a plasticizer,
or other excipients used in pharmaceutical coating
compositions.
Methods of Treatment
[0138] Some embodiments of the present invention include methods of
treating bacterial infections with the compounds and compositions
comprising compounds described herein. Some methods include
administering a compound, composition, pharmaceutical composition
described herein to a subject in need thereof. In some embodiments,
a subject can be an animal, e.g., a mammal, a human. In some
embodiments, the bacterial infection comprises a bacteria described
herein. As will be appreciated from the foregoing, methods of
treating a bacterial infection include methods for preventing
bacterial infection in a subject at risk thereof.
[0139] In some embodiments, the subject is a human.
[0140] Further embodiments include administering a combination of
compounds to a subject in need thereof. A combination can include a
compound, composition, pharmaceutical composition described herein
with an additional medicament.
[0141] Some embodiments include co-administering a compound,
composition, and/or pharmaceutical composition described herein,
with an additional medicament. By "co-administration," it is meant
that the two or more agents may be found in the patient's
bloodstream at the same time, regardless of when or how they are
actually administered. In one embodiment, the agents are
administered simultaneously. In one such embodiment, administration
in combination is accomplished by combining the agents in a single
dosage form. In another embodiment, the agents are administered
sequentially. In one embodiment the agents are administered through
the same route, such as orally. In another embodiment, the agents
are administered through different routes, such as one being
administered orally and another being administered i.v.
[0142] Examples of additional medicaments include an antibacterial
agent, antifungal agent, an antiviral agent, an anti-inflammatory
agent and an anti-allergic agent.
[0143] Some embodiments include a combination of the compounds,
compositions and/or pharmaceutical compositions described herein
with an additional agent, wherein the additional agent comprises a
.beta.-lactamase inhibitor. Non-limiting examples of
.beta.-lactamase inhibitors include clavulanic acid, tazobactam,
sulbactam, RPX-7009, NXL104, MK-7655, BAL-29880, SYN-2190, BLI-489,
AM-112, and ME1071. In various embodiments, the .beta.-lactamase
inhibitor is a class A, B, C, or D .beta.-lactamase inhibitor. An
example of a class B .beta.-lactamase inhibitor includes ME1071
[Antimicrob. Agents Chemother. (2010), 54(9), 3625-3629]. Some
embodiments include co-administering the compound, composition or
pharmaceutical composition described herein with one or more
additional agents.
Indications
[0144] The compounds and compositions comprising monocyclic
.beta.-lactam derivatives described herein can be used to treat
bacterial infections. Bacterial infections that can be treated with
the compounds, compositions and methods described herein can
comprise a wide spectrum of bacteria.
[0145] Examples of bacterial infections include Pseudomonas
aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans,
Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas
maltophilia, Burkholderia cepacia, Aeromonas hydrophilia,
Escherichia coli, Citrobacter freundii, Salmonella typhimurium,
Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis,
Shigella dysenteriae, Shigella flexneri, Shigella sonnei,
Enterobacter cloacae, Enterobacter aerogenes, Klebsiella
pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella
tularensis, Morganella morganii, Proteus mirabilis, Proteus
vulgaris, Providencia alcalifaciens, Providencia rettgeri,
Providencia stuartii, Acinetobacter baumannii, Acinetobacter
calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica,
Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia,
Bordetella pertussis, Bordetella parapertussis, Bordetella
bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae,
Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus
ducreyi, Pasteurella multocida, Pasteurella haemolytica,
Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus,
Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi,
Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila,
Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria
meningitidis, Kingella, Moraxella, Gardnerella vaginalis,
Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A
homology group, Bacteroides vulgatus, Bacteroides ovalus,
Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides
eggerthii, Bacteroides splanchnicus, Clostridium difficile,
Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium
intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae,
Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus
agalactiae, Streptococcus pyogenes, Enterococcus faecalis,
Enterococcus faecium, Staphylococcus aureus, Staphylococcus
epidermidis, Staphylococcus saprophyticus, Staphylococcus
intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus
haemolyticus, Staphylococcus hominis, or Staphylococcus
saccharolyticus.
[0146] To further illustrate this invention, the following examples
are included. The examples should not, of course, be construed as
specifically limiting the invention. Variations of these examples
within the scope of the claims are within the purview of one
skilled in the art and are considered to fall within the scope of
the invention as described, and claimed herein. The reader will
recognize that the skilled artisan, armed with the present
disclosure, and skill in the art is able to prepare and use the
invention without exhaustive examples.
EXAMPLES
Compound Preparation
[0147] The starting materials used in preparing the compounds of
the invention are known, made by known methods, or are commercially
available. It will be apparent to the skilled artisan that methods
for preparing precursors and functionality related to the compounds
claimed herein are generally described in the literature. The
skilled artisan given the literature and this disclosure is well
equipped to prepare any of the compounds.
[0148] It is recognized that the skilled artisan in the art of
organic chemistry can readily carry out manipulations without
further direction, that is, it is well within the scope and
practice of the skilled artisan to carry out these manipulations.
These include reduction of carbonyl compounds to their
corresponding alcohols, oxidations, acylations, aromatic
substitutions, both electrophilic and nucleophilic,
etherifications, esterification and saponification and the like.
These manipulations are discussed in standard texts such as March's
Advanced Organic Chemistry: Reactions, Mechanisms, and Structure
7.sup.th Ed., John Wiley & Sons (2013), Carey and Sundberg,
Advanced Organic Chemistry 5.sup.th Ed., Springer (2007),
Comprehensive Organic Transformations: A Guide to Functional Group
Transformations, 2.sup.nd Ed., John Wiley & Sons (1999) and the
like.
[0149] The skilled artisan will readily appreciate that certain
reactions are best carried out when other functionality is masked
or protected in the molecule, thus avoiding any undesirable side
reactions and/or increasing the yield of the reaction. Often the
skilled artisan utilizes protecting groups to accomplish such
increased yields or to avoid the undesired reactions. These
reactions are found in the literature and are also well within the
scope of the skilled artisan. Examples of many of these
manipulations can be found for example in T. Greene and P. Wuts
Protective Groups in Organic Synthesis, 4th Ed., John Wiley &
Sons (2007).
[0150] Trademarks used herein are examples only and reflect
illustrative materials used at the time of the invention. The
skilled artisan will recognize that variations in lot,
manufacturing processes, and the like, are expected. Hence the
examples, and the trademarks used in them are non-limiting, and
they are not intended to be limiting, but are merely an
illustration of how a skilled artisan may choose to perform one or
more of the embodiments of the invention.
[0151] (.sup.CH) nuclear magnetic resonance spectra (NMR) were
measured in the indicated solvents on a Bruker NMR spectrometer
(Avance TM DRX300, 300 MHz for .sup.1H or Avance TM DRX500, 500 MHz
for .sup.1H) or Varian NMR spectrometer (Mercury 400BB, 400 MHz for
.sup.1H). Peak positions are expressed in parts per million (ppm)
downfield from tetramethylsilane. The peak multiplicities are
denoted as follows, s, singlet; d, doublet; t, triplet; q, quartet;
ABq, AB quartet; quin, quintet; sex, sextet; sep, septet; non,
nonet; dd, doublet of doublets; d/ABq, doublet of AB quartet; dt,
doublet of triplets; td, triplet of doublets; dq, doublet of
quartets; m, multiplet.
[0152] The following abbreviations have the indicated meanings:
[0153] brine=saturated aqueous sodium chloride
[0154] CDCl.sub.3=deuterated chloroform
[0155] DCC=N,N'-dicyclohexylcarbodiimide
[0156] DCM=dichloromethane
[0157] DEAD=diethyl azodicarboxylate
[0158] DMF=N,N-dimethylformamide
[0159] DMSO-d.sub.6=deuterated dimethylsulfoxide
[0160] ESIMS=electron spray mass spectrometry
[0161] EtOAc=ethyl acetate
[0162] HCl=hydrochloric acid
[0163] K.sub.2CO.sub.3=potassium carbonate
[0164] LC/MS=liquid chromatography-mass spectrometry
[0165] MeOH=methanol
[0166] MTBE=methyl tert-butyl ether
[0167] NMR=nuclear magnetic resonance
[0168] PCl.sub.5=phosphorus pentachloride
[0169] Pd/C=palladium on carbon
[0170] PPh.sub.3=triphenylphosphine
[0171] rt=room temperature
[0172] TFA=trifluoroacetic acid
[0173] THF=tetrahydrofuran
[0174] TLC=thin layer chromatography
[0175] The following example schemes are provided for the guidance
of the reader, and collectively represent an example method for
making the compounds provided herein. Furthermore, other methods
for preparing compounds of the invention will be readily apparent
to the person of ordinary skill in the art in light of the
following reaction schemes and examples. The skilled artisan is
thoroughly equipped to prepare these compounds by those methods
given the literature and this disclosure. The compound numberings
used in the synthetic schemes depicted below are meant for those
specific schemes only, and should not be construed as or confused
with same numberings in other sections of the application. Unless
otherwise indicated, all variables are as defined above.
General Procedures
[0176] Intermediates for the .beta.-lactam core fragment are
synthesized as shown in general Schemes 1-4. Preparations of
requisite .beta.-hydroxy-.alpha.-aminoacids can be achieved by some
of the methods described in the literature [Tetrahedron Letters
(1986), 27(25), 2793-2796; Journal of Biological Chemistry (1949),
178(2), 709-714; Aktiengesellschaft, D., Process for the production
of beta-hydroxy-alpha-aminocarboxylic acids, A. Kleemann, B.
Lehmann, K. Deller--U.S. Pat. No. 4,486,600, Dec. 4, 1984]. When
necessary desired single stereoisomers can be obtained by
resolution of salts with optically pure amines or acids as
applicable [Slusarchyk, William A.; Koster, William H., [3
S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[2,2-dimethyl-4-oxo-1-(sulfooxy)-3--
azetidinyl]amino]-2-oxoethylidene]-amino]oxy]acetic acid and
intermediate, U.S. Pat. No. 4,638,061, Jan. 20, 1987.; The Journal
of Peptide Research (1998), 52(2), 143-15]. Alternatively optically
pure starting materials or chiral catalysts may be employed in
stereoselective synthetic sequences leading to single stereoisomers
[Tetrahedron (1983), 39(12), 2085-2092; Tetrahedron (1988), 44(17),
5277-5292; Journal of the American Oil Chemists' Society (1997),
74(11), 1345-1360; Tetrahedron: Asymmetry (2001), 12(3), 481-486;
The Journal of Organic Chemistry (2002), 68(1), 177-179].
[0177] In following schemes, P.sub.1-P.sub.7 denotes typical
protecting groups compatible with requisite chemistry and L denotes
typical leaving groups. In cases when unprotected intermediates are
suitable for requisite transformations P.sub.1-P.sub.7 may also
denote hydrogen.
[0178] Preparation of the .beta.-lactam core intermediates X and XI
from bis N-protected glycine ester (II) or mono N-protected glycine
ester (V) is shown in Scheme 1.
##STR00008##
[0179] Scheme 1 describes a method for preparation of the
.beta.-lactam core intermediates X and XI by either starting with
bis N-protected glycine ester (II) [Tetrahedron (1988), 44(12),
3685-3692] which is first reacted with ketone (III) followed by bis
deprotection of the amine and then monoprotection to give
.beta.-hydroxyacid (VI). .beta.-hydroxyacid (VI) can also be
synthesized starting with the mono N-protected glycine ester (II)
[Tetrahedron Letters (1986), 27(25), 2789-2792; Sundeen, J. E.
(1987, July). Preparation of monosulfactams as antibiotics. Eur.
Pat. Appl. EP0229012, Squibb and Sons, Inc., USA; Sundeen, J. E.
(1987, July). O-Sulfated spiro .beta.-lactam hydroxamic acids. U.S.
Pat. No. 4,680,388, Squibb and Sons, Inc., USA] through a similar
path without the need to deprotect/protect the amine.
.beta.-hydroxyacid (VI) is then coupled with a protected
hydroxylamine (VII) followed by either cyclization by the Mitsunobu
reaction or 2-picoline (or pyridine)-SO.sub.3 complex to give the
protected .beta.-lactam (IX). IX can be first N-deprotected to give
intermediate X or further O-deprotected to give intermediate
XI.
[0180] Another preparation of the .beta.-lactam core intermediates
X and XI from copper glycinate (XII) is shown in Scheme 2.
##STR00009##
[0181] Scheme 2 describes a method for preparation of the
.beta.-lactam core intermediates X and XI which starts with the
alkylation [Hoppe-Seyler's Zenschrift fuer Physiologische Chemie
(1961), 327, 41-48] of a copper(II)glycinate derivative (XII) with
ketone (III) to yield a .beta.-hydroxyacid (IV). .beta.-hydroxyacid
(VI) is N-protected before then being coupled with a protected
hydroxylamine (VII) followed by either cyclization by the Mitsunobu
reaction or 2-picoline (or pyridine)-SO.sub.3 complex to give the
protected .beta.-lactam (XIII) XIII can be first N-deprotected to
give intermediate XIV or further O-deprotected to give intermediate
XV. All three racemic .beta.-lactams can be optically resolved by
known procedures [Slusarchyk, William A.; Koster, William H.,
[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[2,2-dimethyl-4-oxo-1-(sulfooxy)--
3-azetidinyl]amino]-2-oxoethylidene]-amino]oxy]acetic acid and
intermediate, U.S. Pat. No. 4,638,061, Jan. 20, 1987.; The Journal
of Peptide Research (1998), 52(2), 143-15].
[0182] Preparation of the .beta.-lactam core intermediate XIX from
mono N-protected glycine ester (V) and an aminoxyacetic acid
derivative (XVI) is shown in Scheme 3.
##STR00010##
[0183] Scheme 3 describes a method [Tetrahedron Letters (1986),
27(25), 2789-2792; Sundeen, J. E. (1987, July). Preparation of
monosulfactams as antibiotics. Eur. Pat. Appl. EP0229012, Squibb
and Sons, Inc., USA; Sundeen, J. E. (1987, July). O-Sulfated spiro
.beta.-lactam hydroxamic acids. U.S. Pat. No. 4,680,388, Squibb and
Sons, Inc., USA] for preparation of the .beta.-lactam core
intermediate XIX which starts by coupling a N-protected
.beta.-hydroxyacid (VI) with a aminoxyacetic acid derivative (XVI)
to produce XVII which is cyclized either by the Mitsunobu reaction
or 2-picoline (or pyridine)-SO.sub.3 complex to give the protected
.beta.-lactam (XVIII). XVIII is then N-deprotected to give
intermediate XIX.
[0184] Another preparation of the .beta.-lactam core intermediate
XIX from mono N-protected glycine ester (XX) and an
.alpha.-haloacetic acid derivative (XXI) is shown in Scheme 4.
##STR00011##
[0185] Another preparation of the .beta.-lactam core intermediate
XIX is shown above in Scheme 4 with protected .beta.-lactam IX
being first O-deprotected followed by coupling with an
.alpha.-haloacetic acid derivative (XXI) to produce XVIII XVIII is
then N-deprotected to give intermediate XIX.
[0186] General schemes 5-6 describe synthetic routes by which
monocyclic .beta.-lactam intermediates are coupled to N-acyl
sidechain and later converted to final monocyclic .beta.-lactams of
current invention. The following schemes assume proper selection of
orthogonal protecting groups allowing selective unmasking of
requisite functionalities.
[0187] Compounds of Formula I of the present invention can be
prepared as depicted in Scheme 5.
##STR00012## ##STR00013##
[0188] Scheme 5 describes a method [European Journal of Medicinal
Chemistry (1981), 16(4), 307-316] for preparation of monobactam
derivatives (XXXII) from the protected carboxymethoxyiminoacetic
acid intermediate XXVIII XXVIII can be synthesized by coupling
hydroxyimino derivative (XXII or XXIII) with the protected acetic
acid derivative (XXIV) followed any necessary deprotection or by
direct coupling of the aminoxyacetic acid derivative (XXVII) with
glycolic acid derivative (XXVI). XXVIII can then be coupled with
O-protected .beta.-lactam derivative (X) or with unprotected
.beta.-lactam derivative (XI) to ultimately give monobactam
derivative (XXX). The free hydroxy of XXX is then coupled with
protected .alpha.-haloacetic acid derivative (XXI) to yield fully
protected monobactam derivative (XXXI) which can be deprotected to
give the desired final monobactam derivatives (XXXII).
[0189] Compounds of Formula I of the present invention can
alternatively be prepared as depicted in Scheme 6.
##STR00014##
[0190] Scheme 6 describes an alternative method for preparation of
monobactam derivatives (XXXII) by coupling 3-amino-.beta.-lactam
(XIX) with the protected carboxymethoxyiminoacetic acid
intermediate XXVIII to give fully protected monobactam derivative
(XXXI) which can be deprotected to give the desired final
monobactam derivatives (XXXII).
ILLUSTRATIVE COMPOUND EXAMPLES
[0191] Preparation of intermediate (XXXVI) is depicted below in
Scheme 7.
##STR00015##
Step 1-2
[0192] To a suspension of sodium hydride (2.0 g, 60% dispersion in
mineral oil, prewashed with hexane) in anhydrous DMF (150 mL) at
0.degree. C. was added phtalimide (XXXIII) (8.15 g, 50.0 mmol) in
portions. After complete addition, stirring continued for 30 min at
room temperature before adding tert-butyl 2-bromoacetate (XXXIV)
(10.7 g [8 mL], 54.9 mmol). The reaction was stirred for 30 min,
and then the solution was poured on 100 g ice. The precipitate was
filtered and air dried. The crude material was dissolved in
DCM/MeOH (75:10) mixture followed by a 97% solution of hydrazine
hydrate (6.3 mL [64-65% hydrazine], 117 mmol) added at room
temperature (some exothermic heating was observed). The precipitate
was filtered and the filtrate was concentrated under reduced
pressure to yield tert-butyl 2-(aminooxy)acetate (XXXVI) as clear
liquid. (6.9 g, 46.9 mmol, 93.8% yield). ESIMS found
C.sub.6H.sub.13NO.sub.3 m/z 148 (M+H).
[0193] Preparation of intermediate (XLII) is depicted below in
Scheme 8.
##STR00016##
Step 1
[0194] To a solution of
(S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methylbutanoic acid
(XXXVII) (851 mg, 3.65 mmol) in anhydrous THF (20 mL) was added
HOBT (493 mg, 3.65 mmol). The reaction mixture was cooled in a
salt/ice bath to -10.degree. C. which was followed by addition of
DCC (752 mg, 3.65 mmol). The reaction mixture was stirred at
0.degree. C. for 40 min before adding a solution of
O-benzylhydroxylamine (XXXVIII) (538 mg, 4.37 mmol) in THF (5 mL).
Stirring continued 0.degree. C. followed by warming to room
temperature for 1.5 h. To the reaction mixture was added hexane (20
mL), the precipitate was filtered and the filtrate was concentrated
under vacuum. To the oily residue was chromatographed on silica gel
(1:1 EtOAc/hexane) followed by recrystallization from MTBE to
produce (S)-tert-butyl
1-(benzyloxyamino)-3-hydroxy-3-methyl-1-oxobutan-2-ylcarbamate
(XXXIX) (1.002 g, 2.96 mmol, 81.1% yield). ESIMS found
C.sub.17H.sub.26N.sub.2O.sub.5 m/z 339 (M+H).
Step 2
[0195] A solution of (S)-tert-butyl
1-(benzyloxyamino)-3-hydroxy-3-methyl-1-oxobutan-2-ylcarbamate
(XXXIX) (950 mg, 2.81 mmol) and 2-picoline-SO.sub.3 complex (630
mg, 3.64 mmol, freshly prepared) in 10 mL of 2-picoline was stirred
at room temperature for few hours. The solvent was evaporated and
the residue was refluxed with EtOAc (10 mL) and aqueous solution of
potassium carbonate (prepared by dissolving 2.3 g K.sub.2CO.sub.3
in 5 mL water) for few hours. The organic solution was washed with
water, 1 M citric acid solution and dried over anhydrous sodium
sulfate. After evaporation the crude material was purified on a
silica gel cartridge (2:1 hexane/EtOAc) to give (S)-tert-butyl
1-(benzyloxy)-2,2-dimethyl-4-oxoazetidin-3-ylcarbamate (XL) as a
crystalline solid (380 mg, 1.19 mmol, 42.2% yield). ESIMS found
C.sub.17H.sub.24N.sub.2O.sub.4 m/z 321 (M+H).
Step 3
[0196] To a solution of (S)-tert-butyl
1-(benzyloxy)-2,2-dimethyl-4-oxoazetidin-3-ylcarbamate (XL) (450
mg, 1.40 mmol) in EtOH (10 mL) was added 10% Pd/C (50 mg). The
mixture was stirred vigorously under atmospheric pressure of
hydrogen. After 2 h, the catalyst was filtered and solvent was
removed under vacuum to yield (S)-tert-butyl
1-hydroxy-2,2-dimethyl-4-oxoazetidin-3-ylcarbamate (XLI) (340 mg,
1.48 mmol, quantitative yield). ESIMS found
C.sub.10H.sub.18N.sub.2O.sub.4 m/z 231 (M+H).
Step 4
[0197] To a solution (S)-tert-butyl
1-hydroxy-2,2-dimethyl-4-oxoazetidin-3-ylcarbamate (XLI) (108 mg,
0.47 mmol) in DCM (0.5 mL) cooled in an ice-water bath to 0.degree.
C. was added triethylsilane (50 mg, 43.0 mmol) followed by TFA (0.5
mL). The reaction was stirred for 30 min and concentrated under
vacuum. DCM was added and reaction mixture was evaporated to
dryness producing crude
(S)-3-amino-1-hydroxy-4,4-dimethylazetidin-2-one (XLII) which was
used in Example 1, Step 3 without further purification. ESIMS found
C.sub.5H.sub.10N.sub.2O.sub.2 m/z 131 (M+H).
Example 1
[0198] Preparation of
(S,Z)-2-(1-(2-aminothiazol-4-yl)-2-(1-(carboxymethoxy)-2,2-dimethyl-4-oxo-
azetidin-3-ylamino)-2-oxo ethylideneaminooxy) acetic acid (1) is
depicted below in Scheme 14.
##STR00017##
Step 1
[0199] To a solution of ethyl
2-oxo-2-(2-(tritylamino)thiazol-4-yl)acetate (XLIII) (8.3 g, 18.8
mmol) in MeOH (8 mL) was added a solution of methanolic NaOH (19.5
mL, 1.0 M). The solution was refluxed for 10 min (LC/MS shows no
ester present), cooled and filtered. The solid was then suspended
in water followed by addition of 1M HCl (17 mL). The yellow
precipitate was filtered, dissolved in 1,4-dioxane and evaporated
under vacuum to give 2-oxo-2-(2-(tritylamino)thiazol-4-yl)acetic
acid (XLIV) (7.8 g, 18.8 mmol, 100% yield). ESIMS found
C.sub.24H.sub.18N.sub.2O.sub.3S m/z 415 (M+H).
Step 2
[0200] To a -10.degree. C. solution of tert-butyl
2-(aminooxy)acetate (XXXVI) (0.75 g, 5.1 mmol) in DCM (10 mL) was
slowly added a solution of
2-oxo-2-(2-(tritylamino)thiazol-4-yl)acetic acid (XLIV) (2.13 g,
5.1 mmol) in DCM (10 mL). The reaction was stored in a -20.degree.
C. freezer for 3 days. The precipitate was filtered and dried to
produce
(Z)-2-(2-tert-butoxy-2-oxoethoxyimino)-2-(2-(tritylamino)thiazol-4-yl)ace-
tic acid (XLV) as a solid. (2.1 g, 3.9 mmol, 76.5% yield). ESIMS
found C.sub.30H.sub.29N.sub.3O.sub.5S m/z 544 (M+H).
Step 3
[0201] A solution of
(Z)-2-(2-tert-butoxy-2-oxoethoxyimino)-2-(2-(tritylamino)thiazol-4-yl)ace-
tic acid (XLV) (0.55 g, 1.0 mmol) in DCM (3 mL) and cooled in ice
bath was added a solution of PCl.sub.5 in DCM (3.5 mL, 0.35 M) over
a 5 min period. After 30 min, an additional volume of the above
solution PCl.sub.5 in DCM (1.8 mL, 0.18 M) was added and the
reaction was continued for another 15 min at 0.degree. C. To the
reaction mixture was added MTBE and the precipitate formed was
filtered to yield crude (Z)-tert-butyl
2-(2-chloro-2-oxo-1-(2-(tritylamino)thiazol-4-yl)ethylideneaminooxy)
acetate (0.55 g, 0.98 mmol, 97.9% yield) which was used in Step 4
without further purification.
Step 4
[0202] To a solution of
(S)-3-amino-1-hydroxy-4,4-dimethylazetidin-2-one (XLII) (76 mg,
0.58 mmol) in THF (1 mL) cooled in an ice bath was added
triethylamine (67 mg, 0.66 mmol), followed by crude (Z)-tert-butyl
2-(2-chloro-2-oxo-1-(2-(tritylamino)thiazol-4-yl)ethylideneaminooxy)aceta-
te (130 mg, 0.23) in THF (1.5 mL). The reaction was stirred for 15
min before the solution was partitioned between EtOAc and 1 M
citric acid. The organic phase was washed with water, dried over
sodium sulfate and evaporated. The crude oil (190 mg) was purified
by silica gel chromatography (3:1 EtOAc/hexane) to give
(S,Z)-tert-butyl
2-(2-(1-hydroxy-2,2-dimethyl-4-oxoazetidin-3-ylamino)-2-oxo-1-(2-(trityla-
mino)thiazol-4-yl)ethylideneaminooxy)acetate (XLVI). (50 mg, 0.077
mmol, 33.2% yield). ESIMS found C.sub.35H.sub.37N.sub.5O.sub.6S m/z
656 (M+H).
Step 5
[0203] To a solution of (S,Z)-tert-butyl
2-(2-(1-hydroxy-2,2-dimethyl-4-oxoazetidin-3-ylamino)-2-oxo-1-(2-(trityla-
mino)thiazol-4-yl)ethylideneaminooxy)acetate (XLVI) (100 mg, 0.152
mmol) in DMF (1 mL) was added potassium carbonate (23 mg, 0.17)
followed by tert-butylbromoacetate (XLVII) (30 mg, 0.077 mmol) The
reaction was stirred for 1.5 h at room temperature before an
additional portion of tert-butylbromoacetate (XLVII) (15 mg, 0.038
mmol) was added and stirring was continued for 30 min. The reaction
was partitioned between EtOAc/hexane/water and the organic phase
was washed with water and dried over sodium sulfate. The residue
was purified on silica gel (hexane/EtOAc) to produce
(S,Z)-tert-butyl
2-(2-(1-(2-tert-butoxy-2-oxoethoxy)-2,2-dimethyl-4-oxoazetidin-3-ylamino)-
-2-oxo-1-(2-(tritylamino)thiazol-4-yl)ethylideneaminooxy)acetate
(XLVIII) (93 mg, 0.121 mmol, 79.5% yield). ESIMS found
C.sub.41H.sub.47N.sub.5O.sub.8S m/z 770 (M+H).
Step 6
[0204] To a solution of (S,Z)-tert-butyl
2-(2-(1-(2-tert-butoxy-2-oxoethoxy)-2,2-dimethyl-4-oxoazetidin-3-ylamino)-
-2-oxo-1-(2-(tritylamino)thiazol-4-yl) ethylideneaminooxy)acetate
(XLVIII) (93 mg, 0.121 mmol) in ethylene chloride (2 mL) was added
a mixture of ethylene chloride/TFA (4 mL) while cooling in an ice
bath. The reaction was warmed to room temperature and stirred until
no partial deprotection products can be observed by LCMS. Reaction
mixture was concentrated under vacuum before diisopropylether was
added. The precipitate was filtered yielding the crude product. The
crude material was dissolved in water (1 mL) and filtered. The
filtrate was freeze-dried to produce
(S,Z)-2-(1-(2-aminothiazol-4-yl)-2-(1-(carboxymethoxy)-2,2-dimethyl-4-oxo-
azetidin-3-ylamino)-2-oxoethylideneaminooxy)acetic acid (1) as the
trifluoroacetate salt (59 mg, 0.111 mmol, 92.1% yield). .sup.1H NMR
(D.sub.2O/TFA-d, 500 MHz) .delta. ppm 1.13 (s, 3H), 1.33 (s, 3H),
4.42 (s, 2H), 4.54 (s, 1H), 4.61 (s, 2H), 6.90 (s, 1H); ESIMS found
C.sub.41H.sub.47N.sub.5O.sub.8S m/z 437.9 (M+Na).sup.+.
[0205] Illustrative compounds of Formula (I) are shown in Table
1.
TABLE-US-00001 TABLE 1 1 ##STR00018## 2 ##STR00019## 3 ##STR00020##
4 ##STR00021## 5 ##STR00022## 6 ##STR00023## 7 ##STR00024## 8
##STR00025## 9 ##STR00026## 10 ##STR00027## 11 ##STR00028## 12
##STR00029## 13 ##STR00030## 14 ##STR00031## 15 ##STR00032## 16
##STR00033## 17 ##STR00034## 18 ##STR00035## 19 ##STR00036## 20
##STR00037## 21 ##STR00038## 22 ##STR00039## 23 ##STR00040## 24
##STR00041## 25 ##STR00042## 26 ##STR00043## 27 ##STR00044## 28
##STR00045## 29 ##STR00046## 30 ##STR00047## 31 ##STR00048## 32
##STR00049## 33 ##STR00050## 34 ##STR00051## 35 ##STR00052## 36
##STR00053## 37 ##STR00054## 38 ##STR00055## 39 ##STR00056##
Example 2
[0206] Potency and spectrum of compound 1 was determined using the
panel of isogenic engineered strains, each containing a plasmid
carrying a cloned gene expressing a .beta.-lactamase enzyme. The
strain that contained the empty vector was included to evaluate the
impact of individual .beta.-lactamases on microbiological activity
of compound 1 vs comparator antibiotics. The host strain was
wild-type strain of Escherichia coli, ECM5497. The vector plasmid
was pUCP24. Microbiological activity is defined as Minimal
inhibitory concentration (MIC), or the lowest concentration of
antibiotics, at which the visible growth of the organism is
completely inhibited. MIC was assessed using broth microdilution
method as recommended by the NCCLS (National Committee for Clinical
Laboratory Standards. Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria that Grow Aerobically--4.sup.th
Edition. Approved Standard NCCLS Document M7-A4, Vol. 17, No. 2,
NCCLS, Wayne, Pa., January 1997). In this assay multiple dilutions
of drugs are being tested for the ability to inhibit growth of the
test bacterial strains. The MIC assay is performed in microtiter
plates. Antibiotics are diluted two-fold in the x axis, each column
containing a single concentration of antibiotic. The assay is
performed in MHB with a final bacterial inoculum of
5.times.10.sup.5 CFU/mL (from an early-log phase culture).
Microtiter plates are incubated during 20 h at 35.degree. C. and
are read using a microtiterplate reader (Molecular Devices) at 650
nm as well as visual observation using a microtiter plate reading
mirror. The MIC is defined as the lowest concentration of
antibiotics at which the visible growth of the organism is
completely inhibited. Results are presented in Tables 2 and 3.
[0207] Table 2. Activity of Compound 1 and comparator antibiotics
against E. coli strains expressing individual
.beta.-lactamases.
TABLE-US-00002 TABLE 2 .beta.-lactamase MIC (mg/L) Strain Plasmid
class Compound 1 AZTREONAM TIGEMONAM CARUMONAM CEFTAZIDIME ECM6704
pUCP24 vector 2 0.125 0.25 .ltoreq.0.06 0.125 ECM6694
pUCP24::CTX-M-15 A, ESBL 1 32 2 0.125 16 ECM6718 pUCP24::SHV-5 A,
ESBL 4 16 32 2 8 ECM6713 pUCP24::TEM-10 A, ESBL 16 >64 >64 4
65 ECM6701 pUCP24::KPC-2 A, carbapenemase 1 16 0.5 0.25 4 ECM6715
pUCP24::AmpC C 2 8 4 4 16 ECM6716 pUCP24::OXA-48 D 2 0.125 0.25
.ltoreq.0.06 0.125 ECM6703 pUCP24::NDM-1 B 1 .ltoreq.0.06 0.25
.ltoreq.0.06 >64 ECM6711 pUCP24::VIM-1 B 1 .ltoreq.0.06 0.25
.ltoreq.0.06 >64 ECM6706 pUCP24::SME-2 A, carbapenemase 1 >64
0.5 0.125 1 ECM6696 pUCP24::NMC-A A, carbapenemase 1 64 0.5 0.25
0.5
[0208] Table 3. Ratios of MIC of each antibiotic vs vector
alone
TABLE-US-00003 TABLE 3 .beta.-lactamase MIC (mg/L) Strain Plasmid
class Compound 1 AZTREONAM TIGEMONAM CARUMONAM CEFTAZIDIME ECM6704
pUCP24 vector 1 1 1 1 1 ECM6694 pUCP24::CTX-M-15 A, ESBL 0.5 256 8
2 128 ECM6718 pUCP24::SHV-5 A, ESBL 2 128 128 32 64 ECM6713
pUCP24::TEM-10 A, ESBL 8 512 256 64 512 ECM6701 pUCP24::KPC-2 A,
carbapenemase 0.5 128 2 5 32 ECM6715 pUCP24::AmpC C 1 64 16 64 128
ECM6716 pUCP24::OXA-48 D 1 1 2 1 1 ECM6703 pUCP24::NDM-1 B 0.5 0.5
2 1 512 ECM6711 pUCP24::VIM-1 B 0.5 0.5 1 1 512 ECM6706
pUCP24::SME-2 A, carbapenemase 0.5 512 2 2 8 ECM6696 pUCP24::NMC-A
A, carbapenemase 0.5 512 2 4 4
[0209] Table 2 contains MICs of compound 1 and comparator
antibiotics for each test strain and Table 3 contains MIC ratios vs
vector only control (strain ECM6704). .beta.-Lactamases present in
the test panel belonged to all four currently described classes of
enzymes, A, B, C and D. These .beta.-lactamases also represent the
major groups of the most relevant enzymes.
[0210] The results indicate that out of several .beta.-lactams
tested (monobactams aztreonam, tigemonam and carumonam and
cephalosporin ceftazidime), compound 1 was the least affected by
.beta.-lactamases. Specifically, other than TEM-10, no enzyme in
this panel affected the potency of compound 1. Similar to other
monobactams, it was not affected by class B or class D enzymes. But
unlike other monobactams, it was not affected by the majority of
class A and class C enzymes as well. The only enzyme in this panel
that had some effect on activity of compound 1 was TEM-10. Still
even the effect of TEM-10 on compound 1 was still much less than
that on other monobactams or ceftazidime.
[0211] The term "comprising" as used herein is synonymous with
"including," "containing," or "characterized by," and is inclusive
or open-ended and does not exclude additional, unrecited elements
or method steps.
* * * * *